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- EMDB-61108: Cryo-EM structure of human Alpha-7 nicotinic acetylcholine receptor -

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Basic information

Entry
Database: EMDB / ID: EMD-61108
TitleCryo-EM structure of human Alpha-7 nicotinic acetylcholine receptor
Map data
Sample
  • Complex: AChR7 nicotinic acetylcholine receptor
    • Protein or peptide: Neuronal acetylcholine receptor subunit alpha-7
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CHOLESTEROL
KeywordsReceptors / Inhibitor / MEMBRANE PROTEIN
Function / homology
Function and homology information


sensory processing / dendrite arborization / synaptic transmission involved in micturition / response to acetylcholine / Highly calcium permeable postsynaptic nicotinic acetylcholine receptors / acetylcholine receptor activity / acetylcholine-gated channel complex / chloride channel regulator activity / regulation of amyloid fibril formation / acetylcholine-gated monoatomic cation-selective channel activity ...sensory processing / dendrite arborization / synaptic transmission involved in micturition / response to acetylcholine / Highly calcium permeable postsynaptic nicotinic acetylcholine receptors / acetylcholine receptor activity / acetylcholine-gated channel complex / chloride channel regulator activity / regulation of amyloid fibril formation / acetylcholine-gated monoatomic cation-selective channel activity / short-term memory / acetylcholine receptor signaling pathway / dendritic spine organization / acetylcholine binding / regulation of amyloid precursor protein catabolic process / positive regulation of amyloid-beta formation / synaptic transmission, cholinergic / response to amyloid-beta / negative regulation of amyloid-beta formation / positive regulation of protein metabolic process / negative regulation of tumor necrosis factor production / modulation of excitatory postsynaptic potential / plasma membrane raft / monoatomic ion channel activity / monoatomic ion transport / toxic substance binding / negative regulation of cytokine production involved in inflammatory response / excitatory postsynaptic potential / positive regulation of excitatory postsynaptic potential / negative regulation of canonical NF-kappaB signal transduction / positive regulation of long-term synaptic potentiation / response to nicotine / memory / regulation of membrane potential / synapse organization / intracellular calcium ion homeostasis / cognition / positive regulation of angiogenesis / calcium channel activity / calcium ion transport / transmembrane signaling receptor activity / amyloid-beta binding / chemical synaptic transmission / monoatomic ion transmembrane transport / response to hypoxia / positive regulation of MAPK cascade / learning or memory / positive regulation of ERK1 and ERK2 cascade / postsynaptic membrane / postsynapse / neuron projection / positive regulation of cell population proliferation / synapse / dendrite / endoplasmic reticulum membrane / signal transduction / protein homodimerization activity / membrane / plasma membrane
Similarity search - Function
Nicotinic acetylcholine receptor / Neurotransmitter-gated ion-channel, conserved site / Neurotransmitter-gated ion-channels signature. / Neurotransmitter-gated ion-channel transmembrane domain / Neurotransmitter-gated ion-channel transmembrane region / Neurotransmitter-gated ion-channel transmembrane domain superfamily / Neuronal acetylcholine receptor / Neurotransmitter-gated ion-channel / Neurotransmitter-gated ion-channel ligand-binding domain / Neurotransmitter-gated ion-channel ligand-binding domain superfamily / Neurotransmitter-gated ion-channel ligand binding domain
Similarity search - Domain/homology
Neuronal acetylcholine receptor subunit alpha-7
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsYu R / Zhao Y
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)82122064 China
CitationJournal: Acta Pharm Sin B / Year: 2026
Title: Deep learning-driven discovery and mechanism of action study of a minimalist conopeptide targeting 7 nicotinic acetylcholine receptor.
Authors: Jinghui Zhang / Zhengji Yin / Yue Li / Cheng Ge / Zixuan Zhang / Pu Yuan / Tao Jiang / David J Craik / Yan Zhao / Rilei Yu /
Abstract: Despite extensive structural and functional characterization of the 7 nicotinic acetylcholine receptor, valuable structural insights into its interactions with conopeptides remain limited, thereby ...Despite extensive structural and functional characterization of the 7 nicotinic acetylcholine receptor, valuable structural insights into its interactions with conopeptides remain limited, thereby hindering the rational development of peptide-based modulators for this clinically important receptor subtype. Here, we present an integrated pipeline combining deep learning, structural biology, computational modeling and electrophysiology to accelerate the discovery and optimization of 7 nAChR-targeting conopeptides. To overcome data scarcity, we developed a deep learning model using the ESM-2 protein language framework, enabling efficient screening of 689 disulfide-poor conopeptides. This approach identified SS1, a novel antagonist of 7 nAChR, which was systematically optimized structure-activity relationship studies to yield [ΔQP,S8R]SS1-a minimalist peptide with nanomolar potency (IC = 49.2 nmol/L), enhanced selectivity, and improved stability. Cryo-EM and computational modeling resolved the 3.3 Å resolution structure of 7 nAChR bound to [S8R]SS1, revealing a unique binding mode stabilized by hydrogen bonds, hydrophobic interactions, and glycan contacts, while hybrid receptor conformations (closed/desensitized) elucidated its inhibitory mechanism. This work establishes a transformative deep learning-to-experiment framework for accelerating the discovery and optimization of nature-inspired peptide therapeutics.
History
DepositionAug 8, 2024-
Header (metadata) releaseAug 13, 2025-
Map releaseAug 13, 2025-
UpdateAug 26, 2026-
Current statusAug 26, 2026Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_61108.png

Downloads & links

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Map

FileDownload / File: emd_61108.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.96 Å/pix.
x 320 pix.
= 307.2 Å		0.96 Å/pix.
x 320 pix.
= 307.2 Å		0.96 Å/pix.
x 320 pix.
= 307.2 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.96 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.853
Minimum - Maximum-6.513542 - 8.699759500000001
Average (Standard dev.)-0.00039863068 (±0.22375722)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 307.19998 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_61108_half_map_1.map
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Half map: #1

Fileemd_61108_half_map_2.map
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Sample components

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Entire : AChR7 nicotinic acetylcholine receptor

EntireName: AChR7 nicotinic acetylcholine receptor
Components
  • Complex: AChR7 nicotinic acetylcholine receptor
    • Protein or peptide: Neuronal acetylcholine receptor subunit alpha-7
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CHOLESTEROL

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Supramolecule #1: AChR7 nicotinic acetylcholine receptor

SupramoleculeName: AChR7 nicotinic acetylcholine receptor / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Neuronal acetylcholine receptor subunit alpha-7

MacromoleculeName: Neuronal acetylcholine receptor subunit alpha-7 / type: protein_or_peptide / ID: 1 / Number of copies: 5 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 54.211445 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GEFQRKLYKE LVKNYNPLER PVANDSQPLT VYFSLSLLQI MDVDEKNQVL TTNIWLQMSW TDHYLQWNVS EYPGVKTVRF PDGQIWKPD ILLYNSADER FDATFHTNVL VNSSGHCQYL PPGIFKSSCY IDVRWFPFDV QHCKLKFGSW SYGGWSLDLQ M QEADISGY ...String:
GEFQRKLYKE LVKNYNPLER PVANDSQPLT VYFSLSLLQI MDVDEKNQVL TTNIWLQMSW TDHYLQWNVS EYPGVKTVRF PDGQIWKPD ILLYNSADER FDATFHTNVL VNSSGHCQYL PPGIFKSSCY IDVRWFPFDV QHCKLKFGSW SYGGWSLDLQ M QEADISGY IPNGEWDLVG IPGKRSERFY ECCKEPYPDV TFTVTMRRRT LYYGLNLLIP CVLISALALL VFLLPADSGE KI SLGITVL LSLTVFMLLV AEIMPATSDS VPLIAQYFAS TMIIVGLSVV VTVIVLQYHH HDPDGGKMPK WTRVILLNWC AWF LRMKRP GEDKVRPACQ HKQRRCSLAS VEMSAVAPPP ASNGNLLYIG FRGLDGVHCV PTPDSGVVCG RMACSPTHDE HLLH GGQPP EGDPDLAKIL EEVRYIANRF RCQDESEAVC SEWKFAACVV DRLCLMAFSV FTIICTIGIL MSAPNFVEAV SKDFA

UniProtKB: Neuronal acetylcholine receptor subunit alpha-7

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Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 5 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #4: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 4 / Number of copies: 5 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7koo

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 59900
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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